The Framingham Osteoporosis Study (R01 AR41398 Risk Factors for Age Related Bone Loss), an ancillary study of the Framingham Heart Study, has contributed significantly over the past 25 years to the understanding of genetic and lifestyle factors contributing to osteoporosis, sarcopenia, and fractures. Based on the growing epidemic of obesity, and conflicting data regarding the role of visceral adiposity on musculoskeletal health, in this continuation of the Framingham Osteoporosis Study, we will determine the role of visceral adipose tissue (VAT) on bone density, microarchitecture, and strength, as well as on muscle density, and fracture. We are proposing three aims. In Aim 1, to determine the association between VAT and bone density, microarchitecture, and strength, we will measure VAT using longitudinal whole body DXA scans (a baseline previously obtained, and a follow up to be acquired as part of this project) and perform High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) measurements of the distal radius and tibia, and during a clinic visit of the Framingham Study 3rd Generation Cohort (Gen3). In Aim 2 we will determine the association of VAT and muscle density using longitudinal QCT scans already obtained in the Gen3 Cohort. For both Aim 1 and Aim 2, we will also determine if the effects of VAT on bone density, microarchitecture and strength (Aim 1), and on muscle density (Aim 2), are partly attributable to physical activity levels, inflammation, adipokines, or sex steroid metabolism. In Aim 3, we will perform a Mendelian randomization analysis to obtain an unbiased estimate of the VAT-fracture association by using a genetic risk score (instrumental variable) to predict incident fracture. The proposed study will be the largest investigation of the potentially deleterious effects of visceral adiposity on the musculoskeletal system. Each of our hypotheses is based on preliminary data from our past grant cycle or from other research grants involving the Framingham Study. The project is significant for several reasons. First, obesity has become one of the most important health problems in the U.S. Second, the precise role of visceral adiposity on the musculoskeletal system has not been previously investigated, and the proposed work will fill this gap, especially with longitudinal data on VAT and to be obtained longitudinal measures of muscle density using existing CT scans. Third, we will investigate potential underlying mechanisms for the effects of VAT on the musculoskeletal system. Finally we will obtain an unbiased estimate of the VAT-fracture association using Mendelian randomization analysis. Overall, the results of this study will provide the best available data on the effects of visceral adiposity on the musculoskeletal system.